The present invention relates to a method of preparing pharmacologically active oxazolidinones and various intermediates used in the method. The oxazolidinone derivatives are useful as broad spectrum antimicrobial agents which are effective against a variety of human and veterinary pathogens.
Compounds that contain the 5-acetamidomethyl-oxazolidinone moiety are well known to persons skilled in the art as pharmacologically useful antibacterial agents. For example, U.S. Pat. Nos. 5,164,510, 5,182,403, and 5,225,565 disclose antibacterial 5xe2x80x2-indolinyl-oxazolidinones, 3-(5xe2x80x2-indazolyl)-oxazolidinones, and 3-(fused-ring substituted)phenyl-oxazolidinones, respectively. Similarly, U.S. Pat. Nos. 5,231,188 and 5,247,090 disclose several tricyclic [6.5.5] and [6.6.5]-fused ring-oxazolidinones which are useful pharmaceutical agents. International Publication WO93/09103 discloses antibacterial mono- and di-halophenyl-oxazolidinones.
Persons skilled in the art use two primary methods to prepare the 5-acetamidomethyl-oxazolidinone moiety of these therapeutic agents. The first method involves condensation of an aromatic carbamate (Arxe2x80x94HNxe2x80x94C(xe2x95x90O)xe2x80x94OR) or aromatic isocyanate (Arxe2x80x94Nxe2x95x90Cxe2x95x90O) with a halopropanediol or another nitrogen-free three-carbon reagent to provide an intermediate oxazolidinone having a hydroxymethyl substituent at the C-5 position of the oxazolidinone. The hydroxyl group then is replaced by an acetamido group to give a pharmacologically active 5-acetamidomethyl-oxazolidinone.
Many variants of this two-step process have been developed, and examples are illustrated in U.S. Pat. Nos. 4,150,029, 4,250,318, 4,476,136, and 4,340,606, which disclose the synthesis of 5-hydroxymethyl-oxazolidinones from amines (Scheme A). The mixture of enantiomers produced by this process are 
separated by fractional crystallization of their mandelic acid salts. The enantiomerically pure R-diol then is converted into the corresponding 5-(R)-hydroxymethyl-oxazolidinone by condensation with diethylcarbonate in the presence of sodium methoxide. The 5-(R)-hydroxymethyl-oxazolidinone then is aminated, and the resulting amine acylated in subsequent steps.
Likewise, U.S. Pat. No. 4,948,801, J. Med. Chem., 32, 1673 (1989), and Tetrahedron, 45, 1323 (1989) disclose a method of producing oxazolidinones which comprises reacting an isocyanate (Rxe2x80x94Nxe2x95x90Cxe2x95x90O) with (R)-glycidyl butyrate in the presence of a catalytic amount of a lithium bromide-tributylphosphine oxide complex at 135-145xc2x0 C. to produce the corresponding 5-(R)-butyryloxymethyl-oxazolidinone. The butyrate ester then is hydrolyzed in a subsequent step to provide the corresponding 5-(R)-hydroxymethyl-oxazolidinone. The 5-(R)-hydroxymethyl-oxazolidinone then is aminated in a subsequent step.
Similarly, the following references disclose variations of the reaction of a carbamate with glycidyl butyrate: Abstracts of Papers, 206th National Meeting of the American Chemical Society, Chicago, Ill., August, 1993; American Chemical Society: Washington, D.C., 1993; ORGN 089; J. Med. Chem., 39, 673 (1996); J. Med. Chem., 39, 680 (1996); International Publications WO93/09103, WO93/23384, WO95/07271, WO96/13502, and WO96/15130; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F208; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F207; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F206; Abstracts of Papers, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; and American Society for Microbiology: Washington, D.C., 1995, Abstract No. F227. The disclosed reactions use either n-butyllithium, lithium diusopropylamide, or lithium hexamethyldisilazide as the base to generate the nucleophilic anion or the carbamate over a temperature range of xe2x88x9278xc2x0 C. to xe2x88x9240xc2x0 C., followed by addition of the glycidyl butyrate at xe2x88x9278xc2x0 C., and warming to 20-25xc2x0 C. to produce the 5-(R)-hydroxymethyl-oxazolidinones wherein the ester is cleaved during the reaction.
As stated previously, the 5-(R)-hydroxymethyl-oxazolidinones then are aminated and acylated in subsequent steps. For example, International Publication WO95/07271 discloses the ammonolysis of 5-(R)-methylsulfonyloxymethyl-oxazolidinones. Likewise, U.S. Pat. No. 4,476,136 discloses a method of transforming 5-hydroxymethyl-oxazolidinones to the corresponding 5-(S)-aminomethyl-oxazolidinones (X) by treatment with methanesulfonyl chloride, followed by potassium phthalimide, then followed by hydrazine. J. Med. Chem., 32, 1673 (1989) and Tetrahedron, 45, 1323 (1989) disclose a method of transforming 5-hydroxymethyl-oxazolidinones into the corresponding 5-(S)-acetamidomethyl-oxazolidinones by treating with methanesulfonyl chloride or tosyl chloride, followed by the stepwise addition of sodium azide, trimethylphosphite, or platinum dioxide/hydrogen, and acetic anhydride or acetyl chloride to give the desired 5-(S)-acetamidomethyl-oxazolidinone. Likewise, U.S. provisional application Serial No. 60/015,499 discloses a method of preparing 5-(S)-hydroxymethyl-oxazolidinone intermediates, as well as a process to convert these intermediates into 5-aminomethyl-oxazolidinone intermediates which can be acylated to produce pharmacologically active 5-(S)-acetamidomethyl-oxazolidinones. U.S. Pat. No.3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
The second method (Scheme B) involves condensation of an aromatic carbamate (a) or isocyanate (b) with a protected nitrogen (NP)-containing three-carbon reagent to provide an oxazolidinone having the desired amine functionality at the 5-position (e). For example, J. Med. Chem., 33, 2569 (1990) 
discloses the condensation of an isocyanate (b) with racemic glycidyl azide (c, NPxe2x95x90N3) to provide a racemic 5-azidomethyl-oxazolidinone (e). Two subsequent steps are required to convert the racemic azidomethyl-oxazolidinone into a racemic 5-acetamidomethyl-oxazolidinone (e, NPxe2x95x90NHAc), which has antibiotic activity.
International Publication WO99/24393 discloses the reaction of a benzylcarbamoyl amine with three carbon reagents containing amines (NPxe2x95x90NH2), acetamides (NPxe2x95x90NHAc), benzalimines (NPxe2x95x90Nxe2x95x90Cxe2x80x94Ph), or phthalimides. Likewise, Tetrahedron Letters, 37, 7937-40 (1996) discloses a synthesis of acetamidomethyl-oxazolidinones involving the process of condensing a carbamate with 1.1 equivalents of n-butyl lithium (tetrahydrofuran (THF), xe2x88x9278xc2x0 C.), followed by 2 equivalents of S-glycidylacetamide (a, NP=xe2x80x94NHAc), to give the corresponding 5-(S)-acetamidomethyl-oxazolidinone (e). The S-glycidylacetamide can be made by the procedure disclosed in Jacobsen et. al., Tet. Lett. 37, 7937 (1996).
The S-enantiomer of epoxide (c) (Scheme B, NPxe2x95x90NHCO2t-Bu) is well known in the literature, and has been used to prepare oxazolidinones as disclosed in International Publications WO 99/40094 and WO 99/3764, and German Patent application DE 19802239 A1, although by different routes than that shown in Scheme B. The (S)-epoxide (c) has been prepared by a hydrolytic kinetic resolution of the racemic epoxide as disclosed in WO 00/09463, and from R-glycidol as disclosed in WO 93/01174 and J. Med. Chem., 37, 3707 (1994). However, the (S)-epoxide has not been prepared in crystalline form.
The prior art is silent with respect to the use of carbamates (a) or isocyanates (b) in condensations with tert-butylcarbamoyl-, (BOC), or other carbamoyl-protected nitrogen-containing three-carbon reagents (c,d, NPxe2x95x90NCOORxe2x80x3) to directly form oxazolidinones (e). The present invention involves condensation of a carbamate with a carbamoyl-protected derivative of glycidylamine or 3-amino-1-halo-2-propanol. The use of the carbamoyl protecting group, and specifically a tert-butylcarbamoyl (BOC) protecting group, results in a more facile reaction, with a greater yield, compared to the prior art. For example, the analogous acetamide reaction (Scheme B, NPxe2x95x90NHAc) typically requires the use of two equivalents of this reagent for the condensation to occur. In contrast, only 1.3 equivalents of the tert-butylcarbamoyl reagent (Scheme B, NPxe2x95x90NHBOC) is required to obtain comparable yields. The success of such a carbamate condensation is both surprising and unexpected because of the apparent steric hindrance of the tert-butylcarbamoyl group.
The present invention also is directed to the conversion of an isocyanate into the (S)-enantiomer of a 5-substituted-oxazolidinone in a single step. The (S)-enantiomers of 5-substituted-oxazolidinones have greater antibiotic activity than the racemates. U.S. Pat. No. 5,332,754 discloses that racemic 5-acetamidomethyl-oxazolidinones can be synthesized in one step by condensation of a carbamate with racemic glycidyl acetamide in the presence of a base, such as an amine, alkali metal hydroxide, an alkali metal alkoxide, and the like, and that it is preferred to carry out the reaction at an elevated temperature, preferably at a temperature between 90xc2x0 C. and 110xc2x0 C. The patent provides no yields or description of this process in the examples, and evidence indicates that, under these conditions, rearrangement to an undesired side product occurs. Indeed, the examples do not disclose a one-step process, but disclose multi-step routes that are known to those skilled in the art, including mesylation of a 5-hydroxymethyl-oxazolidinone followed by azide displacement, hydrogenation, and acetylation of the amine.
The present method differs in that a) the reaction is between a protected carbamate (I) and an (S)-glydidyl alkylcarbamate (II), an (S)-chlorohydrin alkylcarbamate (IV), or an (S)-chloroacetate alkylcarbamate (V) (Scheme B, NPxe2x95x90NHalkyl); b) the reaction is between an isocyanate (VI) and an (S)-glydidyl alkylcarbamate (II), an (S)-chlorohydrin alkylcarbamate (IV), or an (S)-chloroacetate alkylcarbamate (V) (Scheme B, NPxe2x95x90NHalkyl), and c) the reaction is performed under conditions such that competing rearrangement to the undesired side products is largely suppressed.
The present invention is directed to a method of synthesizing oxazolidinones and intermediate compounds used in the synthesis. As shown in Schemes 1, 2, and 3 below, one aspect of the present invention is to provide an 
S)-oxazolidinone alkylcarbamoyl intermediate of structural formula (III), an (S)-secondary alcohol of structural formula (IV), and an (S)-ester/protected alcohol of structural formula (V), or a salt or hydrate thereof or acceptable salts, hydrates, or pro-compounds thereof, wherein R1 is optionally substituted aryl; R2 is selected from the group consisting of C1-C20 alkyl, C3-C7 cycloalkyl, aryl optionally substituted with one or two C1-C3 alkyl or halogen groups, allyl, 3-methylallyl, 3,3-dimethylallyl, vinyl, styrylmethyl, benzyl optionally substituted on the aryl with one or two Cl, C1-C4 alkyl, nitro, cyano, or trifluoromethyl groups, 9-fluorenylmethyl, trichloromethylmethyl, 2-trimethylsilylethyl, phenylethyl, 1-adamantyl, diphenylmethyl, 1,1-dimethylpropargyl, 2-furanylmethyl, isobornyl, and hydrogen; R3 is C1-C10 alkyl; R4 is H or C1-C5 alkylcarbonyl; and X is halogen, alkylsulfonyloxy, or arylsulfonyloxy.
Another aspect of the present invention is to provide an (S)-epoxide of structural formula (II), an (S)-oxazolidinone t-butylcarbamoyl intermediate of structural formula (III), an (S)-secondary alcohol of structural formula (IV), and an (S)-ester/protected alcohol of structural formula (V), or acceptable salts, hydrates, or pro-compounds thereof, in crystalline form, and a process of preparing these compounds in crystalline form.
One other aspect of the present invention, as shown in Scheme 4, is to 
provide a process for the preparation of an (S)-3-carbon carbamoyl alcohol of the structural formula (IV) which comprises (a) contacting a dialkyldicarbonate with an (S)-amino alcohol of formula (VIII) in the presence of a base, such as a tri(alkyl)amine. The (S)-3-carbon carbamoyl alcohol can be isolated in crystalline form after recrystallization.
Yet another aspect of the present invention, as shown in Scheme 5, 
is to provide a process for preparing a se cond ary protected-alcohol of structural formula (V) which comprises contacting an (S)-3-carbon amino alcohol of structural formula (IV) with an acylating agent and a base, such as a tri(alkyl)amine. The (S)-secondary protected-alcohol can be isolated in crystalline form after recrystallization.
Yet another aspect of the present invention, as shown in Scheme 6, 
is to provide a process for the preparation of a (S)-epoxide of structural formula (II) which comprises contacting an (S)-3-carbon amino alcohol of structural formula (IV) or (S)-secondary protected-alcohol of structural formula (V) with a base. The (S)-epoxide can be isolated in crystalline form after chromatography.
Another aspect of the present invention is to provide a process for the production of an (S)-oxazolidinone of structural formula (III) which comprises contacting a carbamate of structural formula (I) with an oxygenated amino reagent selected from the group consisting of an (S)-t-butylcarbamyl secondary alcohol of structural formula (IV), an (S)-t-butylcarbamyl epoxide of structural formula (II), or an (S)-t-butylcarbamyl ester of structural formula (V), in the presence of a lithium cation and a base whose conjugate acid has a pKa greater than about 8.
An additional aspect of the present invention, as shown in Scheme 7, is 
to provide a process for the production of an (S)-3,5-disubstituted-oxazolidinone of the structural formula (X) and (XI) which comprises (a) contacting a carbamate of structural formula (I) with an (S)-protected alcohol of formula (V) in the presence of a lithium cation and a base whose conjugate acid has a pKa of greater than about 8 to provide an (S)-protected-oxazolidinone of the structural formula (III) (see Scheme 2), (b) contacting the reaction product of step (a) with aqueous acid to produce an (S)-oxazolidinone free amine of structural formula (IX), and (c) contacting the product of step (b) with a base, such as a tri(C1-C5 alkyl)amine, and an acylating or thioacylating agent selected from the group consisting of (i) an acid anhydride of the structural formula O(R5)2, (ii) an activated acid of the structural formula R5X to provide (X) or (iii) a dithioester of the structural formula R5S(Cxe2x95x90S)R5 to provide (XI), wherein R5 is C1-C6 alkylcarbonyl, C1-C6 cycloalkylcarbonyl, C1-C6 alkylthiocarbonyl, or C1-C6 cycloalkylthiocarbonyl, and X is halogen, alkylsulfonyloxy, or arylsulfonyloxy.
A further aspect of the present invention is to provide a one pot process for the production of an (S)-oxazolidinone of structural formula (X) and (XI) which comprises (a) contacting a carbamate of formula (I) with either an (S)-t-butylcarbamyl secondary alcohol of the structural formula (IV) or an (S)-t-butylcarbamyl epoxide of the structural formula (II), in the presence of a lithium cation and a base whose conjugate acid has a pKa of greater than about 8, (b) contacting the product of step (a) with aqueous acid, and (c) contacting the reaction product of step (b) with a base, such as a tri(C1-C5 alkyl)amine, and and an acylating or thioacylating agent selected from the group consisting of (i) an acid anhydride of the structural formula O(R5)2, (ii) an activated acid of the structural formula R5X, or (iii) a dithioester of the structural formula R5S(Cxe2x95x90S)R5, wherein R5 is C1-C6 alkylcarbonyl, C1-C6 cycloalkylcarbonyl, C1-C6 alkylthiocarbonyl, or C1-C6 cycloalkylthiocarbonyl, and X is halogen, alkylsulfonyloxy, or arylsulfonyloxy.
As used herein, the terms and phrases have the meanings, definitions, and explanations known in the art. Some of the more commonly used phrases are described in more detail below.
xe2x80x9cAlkylxe2x80x9d refers to a cyclic, branched, or straight chain aliphatic group containing only carbon and hydrogen, for example, methyl, pentyl, and adamantyl. Alkyl groups can be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, aryl, and benzyl. Alkyl groups can be saturated or unsaturated (e.g., containing alkenyl or alkynyl subunits at one or several positions). Typically, alkyl groups contain 1 to about 12 carbon atoms, preferably 1 to about 10, or 1 to about 8 carbon atoms.
xe2x80x9cArylxe2x80x9d refers to a monovalent aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings (e.g., naphthyl or anthryl). Aryl groups can be unsubstituted or substituted with amino, hydroxyl, alkyl, heteroalkyl, alkoxy, halo, mercapto, sulfonyl, nitro, and other substituents. Typically, the aryl group is a substituted single ring compound. For example, the aryl group is a substituted phenyl ring.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d is defined herein to include fluorine, bromine, chlorine, and iodine.
The term xe2x80x9calkoxyxe2x80x9d and xe2x80x9caryloxyxe2x80x9d are defined as xe2x80x94OR, wherein R is alkyl or aryl, respectively.
The term xe2x80x9chydroxyxe2x80x9d is defined as xe2x80x94OH.
The term xe2x80x9caminoxe2x80x9d is defined as xe2x80x94NR2, wherein each R, independently, is alkyl or hydrogen.
The term xe2x80x9calkylcarbonylxe2x80x9d is defined as Rxe2x80x94C(xe2x95x90O)xe2x80x94, where R is alkyl.
The term xe2x80x9calkylthiocarbonylxe2x80x9d is defined as Rxe2x80x94C(xe2x95x90S)xe2x80x94, where R is alkyl.
The term xe2x80x9calkylsulfonyloxyxe2x80x9d is defined as Rxe2x80x94SO3xe2x80x94, where R is alkyl.
The term xe2x80x9carylsulfonyloxyxe2x80x9d is defined as Rxe2x80x94SO3xe2x80x94, where R is aryl.
The oxazolidinone ring system is numbered as follows: 
The present invention is directed both to novel synthetic intermediates and to methods of preparing pharmaceutically active and commercially valuable oxazolidinone antibiotics, as defined below by the following general synthetic schemes. 
Scheme 1 sets forth the reaction between a carbamate (1) and an (S)-epoxide (II) to produce the corresponding (S)-oxazolidinone (III). Carbamates (I) are known to those skilled in the art, or can be readily prepared from known compounds by methods known to those skilled in the art (See example 1). Suitably, R1 is an aryl group, optionally substituted. Preferably, R1 is: 
wherein Q1 is: R10R11N, 
or Q1 and R8 taken together are dihydropyrrolidine, optionally substituted with R12;
Z1 is CH2(CH2)p, CH(OH)(CH2)p, or C(O);
Z2 is(O)S, O, or N(R13);
Z3 is (O)pS or O;
A1 is H or CH3;
A2 is selected from the group consisting of:
a) H,
b) HO,
c) CH3,
d) CH3O,
e) R4OCH2xe2x95x90C(O)NH,
f) R5OC(O)NH,
g) (C1-C3)alkoxycarbonyl,
h) HOCH2,
i) CH3ONH,
j) CH3C(O),
k) CH3C(O)CH2,
l) CH3C(OCH2CH2O), and
m) CH3C(OCH2CH2O)CH2,
or A1xe2x80x94Cxe2x80x94A2 taken together are CH3xe2x80x94C(OCH2CH2O), C(O), or C(xe2x95x90NR22);
R8 is H or F, or is taken together with Q1 as above;
R9 is H or F;
R10 and R11 are taken together with the N atom to form a 3,7-diazabicyclo[3.3.0]octane, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, morpholine or a piperazine group, optionally substituted with R13;
R12 is selected from the group consisting of:
a) CH3C(O)xe2x80x94,
b) HC(O)xe2x80x94,
c) Cl2CHC(O)xe2x80x94,
d) HOCH2C(O)xe2x80x94,
e) CH3SO2xe2x80x94,
f) F2CHC(O)xe2x80x94,
g) H3CC(O)OCH2C(O)xe2x80x94,
h) HC(O)OCH2C(O)xe2x80x94,
i) R21C(O)OCH2C(O)xe2x80x94,
j) H3CCHCH2OCH2C(O)xe2x80x94,
k) benzyl OCH2C(O)xe2x80x94,
l)-m) 
R13 is selected from the group consisting of:
a) R14OC(16)(R17)C(O)xe2x80x94,
b) R15OC(O)xe2x80x94,
c) R8C(O)xe2x80x94,
d) H3CC(O)(CH2)2C(O)xe2x80x94,
e) R19SO2xe2x80x94,
f) HOCH2C(O)xe2x80x94,
g) R20(CH2)2xe2x80x94,
h) R21C(O)OCH2C(O)xe2x80x94,
i) (CH3)2NCH2C(O)NHxe2x80x94,
j) NCCH2xe2x80x94,
k) F2CHCH2xe2x80x94,
l)-m) 
R14 is H, CH3, benzyl, or CH3C(O)xe2x80x94;
R15 is (C1-C3)alkyl, aryl, or benzyl;
R16 and R17, independently, are H or CH3;
R18 is selected from the group consisting of:
a) Hxe2x80x94,
b) (C1-C4)alkyl,
c) aryl(CH2)m,
d) ClH2Cxe2x80x94,
e) Cl2HCxe2x80x94,
f) FH2Cxe2x80x94,
g) F2HCxe2x80x94, and
h) (C3-C6)cycloalkyl;
R19 is selected from the group consisting of:
a) CH3,
b) CH2Cl,
c) CH2CHxe2x95x90CH2,
d) aryl, and
e) CH2CN;
R20 is OH, CH3Oxe2x80x94, or F;
R21 is:
a) CH3xe2x80x94,
b) HOCH2xe2x80x94,
c) aniline, or
d) (CH3)2N-CH2xe2x80x94,
R22 is selected from the group consisting of:
a) HOxe2x80x94
b) CH3O
c) H2Nxe2x80x94
d) CH3OC(O)Oxe2x80x94,
e) CH3C(O)OCH2C(O)Oxe2x80x94,
f) aryl-CH2OCH2C(O)Oxe2x80x94,
g) HO(CH2)2O,
h) CH3OCH2O(CH2)2Oxe2x80x94, and
i) CH3OCH2Oxe2x80x94;
m is 0 or 1;
n is 1-3;
p is 0-2; and
aryl is unsubstituted phenyl or phenyl unsubstituted with one of the following:
a) F,
b) Cl,
c) OCH3,
d) OH,
e) NH2,
f) (C1-C4)alkyl,
g) OC(O)OCH3, or
h) NO2;
and protected forms thereof.
Specific substituted Q1 groups include, but are not limited to, 4-(benzyloxycarbonyl)-1-piperazinyl, 4-morpholinyl, and 4-hydroxyacetylpiperazinyl. Especially preferred R1 groups include 3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl, 3-fluoro-4-(4-morpholinyl)phenyl, 4-(1,1-dioxohexahydro-1xcex6-thiopyran-4-yl)-3-fluorophenyl, 3-fluoro-4-tetrahydro-2H-thiopyran-4-ylphenyl, 3,5-difluoro-4-(4-thiomorpholinyl)phenyl, 3-fluoro-4-(3-thietanyl)phenyl, and 4-(1,1-dioxido-3-thietanyl)-3-fluorophenyl.
R2 is selected from the group consisting of C1-C20 alkyl, C3-C7 cycloalkyl, aryl optionally substituted with one or two C1-C3alkyl or halogen groups, allyl, 3-methylallyl, 3,3-dimethylallyl, vinyl, styrylmethyl, benzyl optionally substituted on the phenyl with one or two Cl, C1-C4 alkyl, nitro, cyano, or trifluoromethyl groups, 9-fluorenylmethyl, trichloromethylmethyl, 2-trimethylsilylethyl, phenylethyl, l-adamantyl, diphenylmethyl, 1,1-dimethylpropargyl, 2-fuiranylmethyl, isobornyl, and hydrogen. Preferably, R2 is methyl. R3 is C1-C10 alkyl, and, preferably, R3 is C4-C7 tertiary alkyl.
The carbamate (I) and S-epoxide (II) are reacted in the presence of a base and a solvent. The identity of the base is not critical as long as the base is capable of deprotonating carbamate (I), i.e., a base whose conjugate acid has a pKa of greater than about 8. A preferred base is selected from the group consisting of an alkoxy group having one through seven carbon atoms; a carbonate; a methyl, sec-butyl or t-butyl carbanion; tri(alkyl)amine, wherein the alkyl group contains 1 through 5 carbon atoms; a conjugate base of carbamate (II); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); N-methylpiperidine; N-methylmorpholine; and, 2,2,2-trichloroethoxide. The most preferred base is an alkoxy group having four or five carbon atoms, particularly t-amylate or t-butoxide. Sodium or potassium bases in combination with a lithium salt (such as, lithium chloride or lithium bromide) can be used to form the lithium cation and base in situ.
The identity of the solvent also is not critical, and includes, for example, cyclic ethers such as tetrahydrofuran (THF), amides such as dimethylformamide (DMF) and dimethylacetamide (DMAC), amines such as triethylamine, acetonitrile, and alcohols such as t-amyl alcohol and t-butyl alcohol. The choice of solvent is related to the solubility of carbamate (I) and the S-epoxide (II), and can be determined easily by those skilled in the art.
Another embodiment of the present invention is set forth in Scheme 2, 
i.e., the reaction between a carbamate (I) with either an (5)-secondary alcohol (IV) or an (S)-ester (V) to provide a corresponding (S)-oxazolidinone (III). This process is performed in the same manner as that previously disclosed for Scheme 1.
A third process to produce the (S)-oxazolidinone (III) is set forth in Scheme 3 and involves a reaction between an isocyanate (VI) with either a (S)-secondary alcohol (IV) to give an (S)-intermediate (Ini) via compound (VII). This process is performed in a similar manner as that previously disclosed for Schemes 1 and 2. 
The three carbon nitrogen containing fragments, i.e., (S)-secondary alcohol (IV), (S)-epoxide (II), and (S)-ester (V), can be produced by1 different routes, as illustrated in Schemes 4, 5, and 6. Scheme 4 illustrates a process of preparing a 
(S)-3-carbon amino alcohol (IV) from an (S)-amino alcohol (VIII) and a dialkyldicarbonate. For the (S)-amino alcohol (VIII), X can be halogen, alkylsulfonyloxy, or arylsulfonyloxy. A preferred X is Cl. The (S)-amino alcohols (VIII) are known to those skilled in the art or can readily be prepared from known compounds by methods disclosed in WO 99/24393 from commercially available S-epichlorohydrin. The (S)-amino alcohol can be isolated in crystalline form after recrystallization. The reaction of dialkyldicarbonate and the (S)-amino alcohol (VIII) is performed as set forth in Example 3.
It should be noted that starting with an enantiomerically pure (S)-amino alcohol (VIII) ultimately yields an enantiomerically pure (S)-protected alcohol (IV), (S)-ester (V), and (S)-epoxide (II). The absolute configuration of the carbon atom in the pharmacologically useful (S)-oxazolidinone compounds (X) and (XI) is xe2x80x9cSxe2x80x9d, and therefore it is preferable to use enantiomerically pure (S)-amino alcohol (VIII) and obtain enantiomerically pure (S)-protected alcohol (IV), see Scheme 4. In the Schemes and the claims, the supra scripted xe2x80x9c-(S)-xe2x80x9d as -C-(S)- denotes the asymmetric carbon atom has the appropriate enantiomeric configuration (S)- such that when this carbon atom becomes part of an (S)-oxazolidinone (III, X, or XI), it is the preferred enantiomer. If any of the chemical sequences of the processes of the present invention begins with an optically impure (racemic) form, rather than an enantiomerically pure form, the products obtained are the corresponding optically impure (racemic) forms.
Scheme 5 illustrates a process for converting an (S)-carbamoyl alcohol 
(IV) to a corresponding (S)-secondary ester protected alcohol (V). To convert an (S)-carbamoyl alcohol (IV) to a corresponding (S)-secondary ester/protected alcohol (V), the (S)-carbamoyl alcohol (IV) is reacted with an appropriate acylating reagent, such as an acyl halide or acyl anhydride, under acylation reaction conditions well known to those skilled in the art. The (S)-secondary protected-alcohol can be isolated in crystalline form after recrystallization. For example, an (S)-carbamoyl alcohol (IV) can be transformed to a corresponding (S)-secondary ester/protected alcohol (V) by reaction with acetic anhydride in triethylamine, as is set forth in Example 4. For the (S)-3-carbon amino alcohol (IV), X can be halogen, alkylsulfonyloxy, or arylsulfonyloxy, and preferably is Cl. For the corresponding corresponding (S)-secondary ester/protected alcohol (V), R4 is C1-C5 alkylcarbonyl and preferably is acetyl. It is preferred that the acylating reagent be selected from the group consisting of an acid anhydride of the formula O(R5)2, wherein R5 is C1-C6 alkylcarbonyl, or an activated acid of the formula R5 X, wherein X can be halogen, alkylsulfonyloxy or arylsulfonyloxy and preferably is xe2x80x94Cl or xe2x80x94Br, and used in conjunction with base, preferably a tri(C1-C5 alkyl)amine. It is more preferred that R5 is acetyl and X is xe2x80x94Cl. Specifically, the more preferred acylating reagent is an acyl anhydride, and it is most preferred that the acyl anhydride is acetic anhydride.
Scheme 6 shows a process of preparing a (S)-epoxide (II) from either 
an (S)-3-carbon amino alcohol (IV) or an (S)-secondary ester/protected alcohol (V). The (S)-epoxide (II) can be obtained by reaction of an (S)-secondary ester/protected alcohol (V) with a base, such as potassium or lithium t-butoxide, in a solvent, such as methanol. The (S)-epoxide can be isolated in crystalline form after chromatography. An (S)-epoxide (II) can be produced from a corresponding (S)-secondary alcohol (IV) by reaction with lithium t-butoxide in methanol at 20xc2x0 C., as is set forth in Example 5. For an (S)-secondary alcohol (IV) or (S)-secondary ester/protected alcohol (V), it is preferred that R4 is acetyl. For either an (S)-3-carbon amino alcohol (IV) or (S)-secondary ester/protected alcohol (V), X can be halogen, alkylsulfonyloxy, or arylsulfonyloxy, and preferably is Cl.
An (S)-oxazolidinone intermediate (III) is readily transformed to the corresponding pharmacologically active (S)-oxazolidinones (X) and (XI), as shown in Scheme 7. (S)-Oxazolidinone intermediate (III) first can be transformed to the 
(S)-oxazolidinone free amine (IX). (S)-oxazolidinone free amine (IX) then is acylated with an appropriate acylating or thioacylating reagent, such as an activated acid, acyl halide, acyl anhydride, or dithioester, under acylation or thioacylation reaction conditions well known to those skilled in the art (see Examples 14 and 16, and WO 00/32599), to produce an (S)-oxazolidinone (X) or (XI) product, respectively.
Alternatively, the transformation from compound (III) to compound (X) or (XI) can be accomplished as a one pot process without isolating amine (IX). It is preferred that the acylating or thioacylating agent is selected from the group consisting of an acid anhydride of the structural formula O(R5)2, an activated acid of the structural formula R5X, and a dithioester of the structural formula R5S(Cxe2x95x90S)R5, wherein R5 is C1-C6 alkylcarbonyl, C1-C6 cycloalkylcarbonyl, C1-C6 alkylthio-carbonyl, or C1-C6, cycloalkylthiocarbonyl, and X is halogen, alkylsulfonyloxy, or arylsulfonyloxy. It is preferred that the acylating agent or thioacylating agent is used in conjunction with a base, such as a tri(C1-C5 alkyl)amine. It is more preferred that R5 is acetyl and X is Cl. Specifically, it is more preferred that the acylating reagent is an acyl anhydride, and most preferably the acyl anhydride is acetic anhydride.
General Methods and Definitions
Reagents were obtained from commercial sources and used without further purification. All temperatures are in degrees Centigrade. When solvent pairs are used, the ratios of solvents used are volume/volume (v/v). When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v). Reactions with moisture sensitive reagents were performed under a nitrogen atmosphere. Concentration of volumes was performed by reduced pressure rotary evaporation. Brine refers to an aqueous saturated sodium chloride solution. Chromatography (column and flash) refers to purification/separation of compounds expressed as (support/eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s). High performance liquid chromatography (HPLC) analysis was performed using a Dionex DX-500 system with UV detection at 229 NM. Thin layer chromatography (TLC) was performed using 250 micron Analtech silica GF plates. CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm downfield from tetramethylsilane (TMS). NMR refers to nuclear magnetic resonance spectroscopy. 1H NMR refers to proton nuclear magnetic resonance spectroscopy with chemical shifts reported in ppm downfield from TMS. [I]22D refers to the angle of plane polarized light (specific optical rotation) at 25xc2x0 C. with the sodium D line (589 A). Mass spectromotry (MS) is expressed as m/e, m/z or mass/charge unit and is obtained using electron impact (EI), chemical ionization (CI) or fast atom bombardment (FAB) techniques. [M+H]+ refers to the positive ion of a parent plus a hydrogen atom. Retention time (RT) is in minutes and refers to the elution time of the compound after injection. IR refers to infrared spectroscopy. FTIR refers to Fourier Transform IR.